Improving the Pediatric Research Federal Review Process

In an era of increasing skepticism of publicly funded research, it remains imperative for researchers to understand the regulatory frameworks and processes that govern pediatric research. Research involving children involves complex regulations that can present challenges to researchers, clinicians, and institutional review board (IRB) members. Designing and conducting pediatric research poses unique ethical challenges, the most notable being defining and categorizing risk appropriately, inherent subjectivity in risk assessment, and navigating complicated federal regulations. A better understanding of these challenges will enhance the efficiency of pediatric research while maintaining essential safeguards.This perspective aims to inform pediatric researchers and clinicians on the federal research review process and outline relevant challenges and recommendations for its improvement.In the United States, pediatric research is governed by the Department of Health and Human Services (DHHS) through its Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA). The Code of Federal Regulations (CFR) is a compendium of rules for these government agencies.1,2 The DHHS regulations are under Title 45, Part 46 with specific pediatric research subsections (Subpart D; 45 CFR 46.404-407).1 The FDA rules are found in Title 21, with pediatric research regulations in 21 CFR 50.51-54.2 When a research protocol is federally funded, DHHS regulations apply. Research protocols, including an FDA-regulated product, follow FDA regulations regardless of federal funding.2This “alphabet soup” of letters and numbers used to categorize pediatric research may be confusing for clinical researchers unfamiliar with this language. Pediatric research is classified into 4 categories, each dependent on assessment of risk and potential for benefit.3 Pediatric research may be classified as (1) minimal risk (with or without direct benefit), (2) greater than minimal risk with the potential for direct benefit, (3) research with a “minor increase in minimal risk,” without direct benefit or (4) research with “more than a minor increase” in risk without potential for direct benefit (Figure 1A). Research in this fourth category must undergo federal review under (45 CFR 46.407; 21 CFR 50.54), often referred to as “407 reviews or panels.” These reviews require extensive collaboration between the institution and federal agencies to coordinate the review, a public hearing, and publication of recommendations (Figure 1B). This process is cumbersome and often avoided by researchers and IRBs. Given that there have been very few protocols reviewed (approximately 15) since the regulations were established in 1991, this review and approval pathway is likely underutilized. Additionally, research teams may choose to modify interventions or eliminate specific procedures that would trigger a 407 review, often due to the lengthy timeline and substantial coordination such reviews entail.Further complicating this risk assessment, all proposed research protocols must be evaluated using component analysis. Each research intervention is analyzed independently to evaluate the risk of that specific intervention and the potential for benefit.4 For example, in a therapeutic trial with an investigational agent with a potential for direct benefit, a research-only biopsy (without the potential for benefit) must be assessed independently to analyze if it represents only a minor increase in risk. The presence of potential for benefit of one research component does not automatically allow an IRB to approve the entire protocol.The risk language (“minor increase” and “more than a minor increase”) in the regulations is inherently subjective and thus variable, presenting a challenge to standardize risk assessments among protocols.5 Variability in risk assessments can exist across IRBs, a challenge for multicenter studies not using a single, central IRB.5 The categorical differences in risk classification among “minimal,” “minor,” and “greater than minor” can be difficult to distinguish (Figure 1C for risk-level examples). To address this problem, the OHRP and FDA should work to align and delineate a single guidance with more comprehensive definitions and risks for common research interventions, comparable to those outlined by the European Union.6The federal 407 review process has been criticized for being inefficient, lacking transparency, and slowing research in rare and devastating diseases.7 One review estimated the median time from submission to study enrollment to be 19 months, with public access to protocols, meeting transcripts, and final review decisions limited by inaccessible historical records and incomplete maintenance of online federal archives.7 This lack of transparency impacts researchers and IRB members who are searching for information on deliberations that occurred during previous reviews, ultimately creating further delay.A comprehensive, publicly accessible governmental database containing information from all 407 previous panels should be established. Meeting transcripts, supporting documents, and expert reports should be posted and maintained, allowing researchers and IRBs to access valuable information that may expedite and increase the quality and efficiency of future reviews. This central database would promote greater transparency, accountability, and trust in the 407 review process.The development and implementation of standardized 407 review submission forms with clear next steps and timelines, similar to investigational new drug applications, can create greater accessibility and clarity for researchers. Some delays surrounding these reviews are due to the time required of institutions to prepare these referrals, and standardized forms could streamline the process. A more efficient review system would minimize delays, reduce the fear and stigma around federal panel reviews, enhance communication among researchers, local IRBs, and federal agencies, and improve the efficiency and oversight of pediatric clinical trials.Pediatric researchers, clinicians, and IRB members examining previous 407 panels may wonder if previous discussions about specific interventions, such as the use of a central venous access device in a placebo intervention arm, may apply to a research protocol they are designing or reviewing. Current federal guidelines do not discuss the applicability of prior federal reviews, which creates confusion and may permit undue risk to participants. As outlined by the FDA and OHRP, each agency maintains the authority to determine the generalizability of a particular research intervention to prevent redundant federal reviews. If the research is sufficiently similar to previously reviewed research, the FDA and OHRP can waive the need for full panel or subcommittee reviews.8 Draft guidance seeking to clarify this process was published in the Federal Register in March 2023, but remains to be finalized (April 2025).8 To date, the federal agencies have not acted on this ability to create general guidance. To improve this process, a formal submission system managed by the FDA and OHRP would allow IRBs to submit such candidate 407 protocols and delineate similarities. The decision to apply this expedited process would remain at the discretion of the FDA and OHRP, but would allow increased efficiency for the federal review and increased agency for researchers and IRBs.There are several other opportunities to improve the review process for pediatric research, which may contain components that are more than a minor increase in risk without the potential for direct benefit. When federal agencies review pediatric research protocols, those agencies should maintain the authority to initiate a federal review and assign the appropriate risk category. This would improve transparency and possibly result in draft guidance surrounding pediatric research interventions, which ultimately may allow safer pediatric research. For future reviews, in addition to background materials and details on specific deliberations, the creation of a brief, standardized, and publicly available summary report may provide a more useful and objective reference for all stakeholders.To maintain the trust of pediatric clinicians, researchers, IRBs, and research participants, the 407 federal review process must be updated to improve transparency and foster efficiency such that researchers and IRBs are motivated to work with the oversight agencies instead of around them. Education of local IRB members, pediatric researchers, and pediatric clinicians through well-developed and transparent federal guidance would safeguard children from undue risk, provide generalizable knowledge that may improve the understanding of pediatric conditions, and the translation of safer and more efficacious research-based interventions to the bedside.